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. 2023 Apr 10;8(7):e165740.
doi: 10.1172/jci.insight.165740.

suPAR links a dysregulated immune response to tissue inflammation and sepsis-induced acute kidney injury

Christian Nusshag  1   2 , Changli Wei  1 , Eunsil Hahm  1 , Salim S Hayek  3 , Jing Li  1 , Beata Samelko  1 , Christoph Rupp  4 , Roman Szudarek  4 , Claudius Speer  2 , Florian Kälble  2 , Matthias Schaier  2 , Florian Uhle  4 , Felix Cf Schmitt  4 , Mascha O Fiedler  4 , Ellen Krautkrämer  2 , Yanxia Cao  1 , Ricardo Rodriguez  1 , Uta Merle  5 , Jesper Eugen-Olsen  6 , Martin Zeier  2 , Markus A Weigand  4 , Christian Morath  2 , Thorsten Brenner  4   7 , Jochen Reiser  1
Affiliations

suPAR links a dysregulated immune response to tissue inflammation and sepsis-induced acute kidney injury

Christian Nusshag et al. JCI Insight. .

Abstract

Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune-derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00-18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune-derived and kidney function-independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell-based kidney inflammation, while suPAR deficiency improves SI-AKI.

Keywords: Clinical practice; Diagnostics; Inflammation; Nephrology; T cells.

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Conflict of interest statement

Conflict of interest: JR is cofounder and shareholder of Walden Biosciences, a biopharmaceutical company that develops novel therapy for kidney diseases. SSH received consulting fees from Walden Biosciences. JEO is CEO, cofounder, and shareholder of ViroGates. CM and MS are cofounders, patent holders (EP 2318020 and US 11,123,368 B2; new extended patent filed [PCT], WO 2020/233776 [published 26/11/2020]), and shareholders of Tolerogenixx.

Figures

Figure 1
Figure 1. Flow chart of study design and data analysis.
AKI, acute kidney injury according to KDIGO criteria; RRT, renal replacement therapy.
Figure 2
Figure 2. Blood suPAR levels discriminate between maximum AKI stages, varying AKI courses, and poor (kidney) outcome in human sepsis at any time within 7 days of sepsis diagnosis.
(A–C) Outcome-related course of serum creatinine (SCr) and soluble urokinase plasminogen activator receptor (suPAR) over 7 days after sepsis diagnosis (0 hours, n = 200; 12 hours, n = 190; 24 hours, n = 190; 48 hours, n = 186; 3 days, n = 177; 4 days, n = 175; 5 days, n = 167; 7 days, n = 155) and (D–F) outcome in relation to suPAR quartiles at baseline. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. NS, P > 0.05. AKI, acute kidney injury; IQR, interquartile range; MAKE7, major adverse kidney events within 7 days of sepsis diagnosis; RRT, renal replacement therapy. Data are reported as box-and-whisker plots (interquartile range, minimum to maximum) (A–C), unadjusted odds ratio (95% CI) (D), and percentage (E and F). One-way ANOVA (A–C) and χ2 (E and F) tests were used for group comparisons.
Figure 3
Figure 3. Elevated blood levels of suPAR are associated with enhanced kidney tissue damage, kidney function impairment, and poor (kidney) outcome in murine sepsis.
Sepsis was induced via i.p. injection of 250 μL cecal slurry (CS) in C57BL/6 WT (n = 16), uPAR-knockout (KO, n = 15), and transgenic C57BL/6 with overexpression of suPAR (OE, n = 14). Glycerol (GLY, 15%) served as control in WT (vehicle control, n = 10). (A) H&E staining of kidneys from different mouse strains 24 hours after sepsis induction. Original magnification, ×40. Scale bar: 100 μm. (B) Maximum serum creatinine (SCr) changes from baseline within 24 hours and (C) urea 24 hours after sepsis induction. (D) suPAR levels at baseline and (E) 24 hours after sepsis induction. (F) IL-6 levels 6 hours after sepsis induction. (G) Survival analysis of different mouse strains. Survival: WT GLY, 10/10 (100%); WT CS, 11/16 (69%); KO CS, 13/15 (87%); OE CS, 7/14 (50%). Data are reported as mean ± SEM. One-way ANOVA test was used for group comparisons (B–F), and the Kaplan-Meier method and log-rank testing were used for survival analyses (G).
Figure 4
Figure 4. Characterization of kidney leukocyte subsets in C57BL/6 WT, uPAR-KO, and transgenic C57BL/6 with overexpression of suPAR reveals a link between increased blood suPAR levels and kidney T cell accumulation, kidney function impairment, and local upregulation of inflammatory cytokines.
(A–D) Strain-dependent characterization of leukocyte subsets by flow cytometry after 24 hours of sepsis induction (left) via i.p. injection of 250 μL cecal slurry (CS) and untreated mice (right). Injection of 15% glycerol (GLY) served as control (vehicle solution). (E) Exemplary double immunofluorescent staining for podocin (green) and CD8+ T cells (red) of kidney tissue from different mouse strains after 24 hours of sepsis. Nuclei were stained with DAPI (blue). Spleen tissue served as positive (primary and secondary antibody) and negative (secondary antibody only) control (data not shown). To quantify kidney immune cell aggregation, the mean cell number was determined from 10 representative high-power fields per animal (see supplemental material). Original magnification, ×40. Scale bar: 100 μm. (F) Correlation analysis of kidney T cells and corresponding blood serum creatinine (SCr) and suPAR levels in WT sepsis. (G) Kidney Luminex analysis of homogenized kidney tissue of untreated WT and suPAR-OE mice. CCL, C-C motif chemokine ligand 3; MFI, median fluorescence intensity; TSP4, thrombospondin 4. Data are reported as mean ± SEM. One-way ANOVA test was used for multiple group comparisons (A–D), correlations were assessed by using Pearson’s correlation analysis (F), and 2-tailed Student’s t test was used for pairwise comparisons (G).
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References

    1. Kellum JA, Prowle JR. Paradigms of acute kidney injury in the intensive care setting. Nat Rev Nephrol. 2018;307(4):2265–2230. - PubMed
    1. Nusshag C, et al. Issues of acute kidney injury staging and management in sepsis and critical illness: a narrative review. Int J Mol Sci. 2017;18(7):1387. doi: 10.3390/ijms18071387. - DOI - PMC - PubMed
    1. Uchino S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294(7):813–818. doi: 10.1001/jama.294.7.813. - DOI - PubMed
    1. Kellum JA, et al. Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2012;138:1–138.
    1. Gaudry S, et al. Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial. Lancet. 2021;397(10281):1293–1300. doi: 10.1016/S0140-6736(21)00350-0. - DOI - PubMed

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